Abstract

Fenofibrate is a selective peroxisome proliferator-activated receptor α (PPARα) activator and is prescribed to treat hyperlipidemia. The mechanism through which PPARα agonists reduce food intake, body weight, and adiposity remains unclear. One explanation for the reduction of food intake is that fenofibrate promotes fatty acid oxidation and increases the production of ketone bodies upon a standard experimental dose of the drug (100~300 mg/kg/day). We observed that low-dose treatment of fenofibrate (30 mg/kg/day), which does not cause significant changes in ketone body synthesis, reduced food intake in Long-Evans Tokushima (LETO) rats. LETO rats are the physiologically normal controls for Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are obese and cholecystokinin (CCK)-A receptor deficient. We hypothesized that the reduced food intake by fenofibrate-treated LETO rats may be associated with CCK production. To investigate the anorexic effects of fenofibrate in vivo and to determine whether CCK production may be involved, we examined the amount of food intake and CCK production. Fenofibrate-treated OLETF rats did not significantly change their food intake while LETO rats decreased their food intake. Treatment of fenofibrate increased CCK synthesis in the duodenal epithelial cells of both LETO and OLETF rats. The absence of a change in the food intake of OLETF rats, despite the increase in CCK production, may be explained by the absence of CCK-A receptors. Contrary to the OLETF rats, LETO rats, which have normal CCK receptors, presented a decrease in food intake and an increase in CCK production. These results suggest that reduced food intake by fenofibrate treatment may be associated with CCK production.

Change of food consumption (A) and body weight gain (B) in LETO and OLETF rats. In LETO rats, the average consumption of the control group was 27±1 g per day while the average consumption of the fenofibrate group was 24±1 g per day (p<0.05). Values are means±SEM. n=5.

Effects of fenofibrate on the expression of PPARα and CCK in the small intestines of LETO and OLETF rats. (A) Relative amounts of PPARα and CCK mRNA were analyzed by RT-PCR in the small intestine of LETO rats. Values shown (means±SEM) are normalized against GAPDH mRNA. n=5. *p<0.05 vs. control. (B) Protein levels of PPARα and CCK were analyzed by western blotting.

Effects of fenofibrate on the expression of PPARα and CCK in Caco-2 cells. (A) The expression of CCK increased dose-dependently with a low-dose treatment of fenofibrate (3, 10 and 30 µM) for 24 h. (B) The expression of CCK in Caco-2 cells was induced by several kinds of PPARα agonists; fenofibrate 100 µM (feno), bezafibrate 100 µM (beza) and clofibrate 250 µM (clo). Experiments shown were repeated three times to confirm reproducibility.